Mutation in FBXO32 causes dilated cardiomyopathy through up-regulation of ER-stress mediated apoptosis.

Endoplasmic reticulum (ER) stress induction of cell death is implicated in cardiovascular diseases. Sustained activation of ER-stress induces the unfolded protein response (UPR) pathways, which in turn activate three major effector proteins. We previously reported a missense homozygous mutation in FBXO32 (MAFbx, Atrogin-1) causing advanced heart failure by impairing autophagy.

Protein arginine methyltransferase 6 mediates cardiac hypertrophy by differential regulation of histone H3 arginine methylation.

Heart failure remains a major cause of hospitalization and death worldwide. Heart failure can be caused by abnormalities in the epigenome resulting from dysregulation of histone-modifying enzymes. While chromatin enzymes catalyzing lysine acetylation and methylation of histones have been the topic of many investigations, the role of arginine methyltransferases has been overlooked.

Protein tyrosine phosphatases in cardiac physiology and pathophysiology.

More than any other organ, the heart is particularly sensitive to gene expression deregulation, often leading in the long run to impaired contractile performances and excessive fibrosis deposition progressing to heart failure. Recent investigations provide evidences that the protein phosphatases (PPs), as their counterpart protein kinases, are important regulators of cardiac physiology and development. Two main groups, the protein serine/threonine phosphatases and the protein tyrosine phosphatases (PTPs), constitute the PPs family.

Rosiglitazone promotes cardiac hypertrophy and alters chromatin remodeling in isolated cardiomyocytes.

Rosiglitazone is an anti-diabetic agent that raised a major controversy over its cardiovascular adverse effects. There is in vivo evidence that Rosiglitazone promotes cardiac hypertrophy by PPAR-γ-independent mechanisms. However, whether Rosiglitazone directly alters hypertrophic growth in cardiac cells is unknown.

Ruboxistaurin attenuates diabetic nephropathy via modulation of TGF-β1/Smad and GRAP pathways.

Objective: To investigate whether ruboxistaurin (a selective PKC-β inhibitor) mediates renoprotective effect via interference with TGF-β1/Smad-GRAP cross-signalling.

Method: Diabetes was induced in rats by a single intraperitoneal injection of streptozotocin (55 mg/kg). Then, the diabetic rats were treated with ruboxistaurin (10 mg/kg, p.

FBXO32, encoding a member of the SCF complex, is mutated in dilated cardiomyopathy.

Background: Dilated cardiomyopathy (DCM) is a common form of cardiomyopathy causing systolic dysfunction and heart failure. Rare variants in more than 30 genes, mostly encoding sarcomeric proteins and proteins of the cytoskeleton, have been implicated in familial DCM to date. Yet, the majority of variants causing DCM remain to be identified.

TLE6 mutation causes the earliest known human embryonic lethality.

Background: Embryonic lethality is a recognized phenotypic expression of individual gene mutations in model organisms. However, identifying embryonic lethal genes in humans is challenging, especially when the phenotype is manifested at the preimplantation stage.

Results: In an ongoing effort to exploit the highly consanguineous nature of the Saudi population to catalog recessively acting embryonic lethal genes in humans, we have identified two families with a female-limited infertility phenotype.

Nuclear Calcium/Calmodulin-dependent Protein Kinase II Signaling Enhances Cardiac Progenitor Cell Survival and Cardiac Lineage Commitment.

Ca(2+)/Calmodulin-dependent protein kinase II (CaMKII) signaling in the heart regulates cardiomyocyte contractility and growth in response to elevated intracellular Ca(2+). The δB isoform of CaMKII is the predominant nuclear splice variant in the adult heart and regulates cardiomyocyte hypertrophic gene expression by signaling to the histone deacetylase HDAC4. However, the role of CaMKIIδ in cardiac progenitor cells (CPCs) has not been previously explored.

Deletion of low molecular weight protein tyrosine phosphatase (Acp1) protects against stress-induced cardiomyopathy.

The low molecular weight protein tyrosine phosphatase (LMPTP), encoded by the ACP1 gene, is a ubiquitously expressed phosphatase whose in vivo function in the heart and in cardiac diseases remains unknown. To investigate the in vivo role of LMPTP in cardiac function, we generated mice with genetic inactivation of the Acp1 locus and studied their response to long-term pressure overload. Acp1(-/-) mice develop normally and ageing mice do not show pathology in major tissues under basal conditions.

Recessive mutations in COL25A1 are a cause of congenital cranial dysinnervation disorder.

Abnormal ocular motility is a common clinical feature in congenital cranial dysinnervation disorder (CCDD). To date, eight genes related to neuronal development have been associated with different CCDD phenotypes. By using linkage analysis, candidate gene screening, and exome sequencing, we identified three mutations in collagen, type XXV, alpha 1 (COL25A1) in individuals with autosomal-recessive inheritance of CCDD ophthalmic phenotypes.

Control of histone H3 phosphorylation by CaMKIIδ in response to haemodynamic cardiac stress.

Heart failure is associated with the reactivation of a fetal cardiac gene programme that has become a hallmark of cardiac hypertrophy and maladaptive ventricular remodelling, yet the mechanisms that regulate this transcriptional reprogramming are not fully understood. Using mice with genetic ablation of calcium/calmodulin-dependent protein kinase II δ (CaMKIIδ), which are resistant to pathological cardiac stress, we show that CaMKIIδ regulates the phosphorylation of histone H3 at serine-10 during pressure overload hypertrophy. H3 S10 phosphorylation is strongly increased in the adult mouse heart in the early phase of cardiac hypertrophy and remains detectable during cardiac decompensation.

Cardiac SERCA2A/B: therapeutic targets for heart failure.

Calcium (Ca(2+)) recycling is key for effective relaxation of the cardiac muscle. Failure to properly recycle calcium through the sarcoplasmic reticulum (SR) results in severe impairment of myocardial relaxation and consequently alteration of the "beat-to-beat" heart rhythm and contractile function. The Sarco(Endo)plasmic reticulum Ca(2+) ATPase (SERCA) is instrumental for recycling cytosolic Ca(2+) into the lumen of the SR.

Mutations in CSPP1, encoding a core centrosomal protein, cause a range of ciliopathy phenotypes in humans.

Ciliopathies are characterized by a pattern of multisystem involvement that is consistent with the developmental role of the primary cilium. Within this biological module, mutations in genes that encode components of the cilium and its anchoring structure, the basal body, are the major contributors to both disease causality and modification. However, despite rapid advances in this field, the majority of the genes that drive ciliopathies and the mechanisms that govern the pronounced phenotypic variability of this group of disorders remain poorly understood.

Epigenetics and chromatin remodeling in adult cardiomyopathy.

The manipulation of chromatin structure regulates gene expression and the flow of genetic information. Histone modifications and ATP-dependent chromatin remodeling together with DNA methylation are dynamic processes that modify chromatin architecture and profoundly modulate gene expression. Their coordinated control is key to ensuring proper cell commitment and organ development, as well as adaption to environmental cues.

Nuclear CaMKII enhances histone H3 phosphorylation and remodels chromatin during cardiac hypertrophy.

Calcium/calmodulin-dependent protein kinase II (CaMKII) plays a central role in pathological cardiac hypertrophy, but the mechanisms by which it modulates gene activity in the nucleus to mediate hypertrophic signaling remain unclear. Here, we report that nuclear CaMKII activates cardiac transcription by directly binding to chromatin and regulating the phosphorylation of histone H3 at serine-10. These specific activities are demonstrated both in vitro and in primary neonatal rat cardiomyocytes.

Mutation in PHC1 implicates chromatin remodeling in primary microcephaly pathogenesis.

Primary microcephaly (PM) is a developmental disorder of early neuroprogenitors that results in reduction of the brain mass, particularly the cortex. To gain fresh insight into the pathogenesis of PM, we describe a consanguineous family with a novel genetic variant responsible for the disease. We performed autozygosity mapping followed by exome sequencing to detect the causal genetic variant.

An evolutionarily acquired genotoxic response discriminates MyoD from Myf5, and differentially regulates hypaxial and epaxial myogenesis.

Despite having distinct expression patterns and phenotypes in mutant mice, the myogenic regulatory factors Myf5 and MyoD have been considered to be functionally equivalent. Here, we report that these factors have a different response to DNA damage, due to the presence in MyoD and absence in Myf5 of a consensus site for Abl-mediated tyrosine phosphorylation that inhibits MyoD activity in response to DNA damage. Genotoxins failed to repress skeletal myogenesis in MyoD-null embryos; reintroduction of wild-type MyoD, but not mutant Abl phosphorylation-resistant MyoD, restored the DNA-damage-dependent inhibition of muscle differentiation.

Critical role of nuclear calcium/calmodulin-dependent protein kinase IIdeltaB in cardiomyocyte survival in cardiomyopathy.

Calcium/calmodulin-dependent protein kinase II (CaMKII) plays a central role in cardiac contractility and heart disease. However, the specific role of alternatively spliced variants of CaMKII in cardiac disease and apoptosis remains poorly explored. Here we report that the deltaB subunit of CaMKII (CaMKIIdeltaB), which is the predominant nuclear isoform of calcium/calmodulin-dependent protein kinases in heart muscle, acts as an anti-apoptotic factor and is a novel target of the antineoplastic and cardiomyopathic drug doxorubicin (Dox (adriamycin)).

Nuclear calcium/calmodulin-dependent protein kinase IIdelta preferentially transmits signals to histone deacetylase 4 in cardiac cells.

Class II histone deacetylases (HDACs) act as repressors of cardiac hypertrophy, an adaptative response of the heart characterized by a reprogramming of fetal cardiac genes. Prolonged hypertrophy often leads to dilated cardiomyopathy and heart failure. Upstream endogenous regulators of class II HDACs that regulate hypertrophic growth are just beginning to emerge.

In vivo regulation of Grp78/BiP transcription in the embryonic heart: role of the endoplasmic reticulum stress response element and GATA-4.

The transcriptional activation of GRP78, which controls multiple signaling pathways of the unfolded protein response, has been used extensively as an indicator for the onset of endoplasmic reticulum stress in tissue culture systems. Here we investigate the mechanism of Grp78 induction during mouse embryonic development. Our results reveal that in transgenic mouse models, reporter gene activity driven by the Grp78 promoter is strongly activated during early embryonic heart development but subsides in later stages.

Phosphorylation-dependent degradation of p300 by doxorubicin-activated p38 mitogen-activated protein kinase in cardiac cells.

p300 and CBP are general transcriptional coactivators implicated in different cellular processes, including regulation of the cell cycle, differentiation, tumorigenesis, and apoptosis. Posttranslational modifications such as phosphorylation are predicted to select a specific function of p300/CBP in these processes; however, the identification of the kinases that regulate p300/CBP activity in response to individual stimuli and the physiological significance of p300 phosphorylation have not been elucidated. Here we demonstrate that the cardiotoxic anticancer agent doxorubicin (adriamycin) induces the phosphorylation of p300 in primary neonatal cardiomyocytes.

New cellular and molecular approaches for the treatment of cardiac disease.

Similar to the kidney in uremia, end-stage cardiac failure is an outcome common to many disparate disease processes including hypertension, various inflammatory pathologies, as well as ischemic loss of tissue. In regard to the heart, cellular and molecular mechanisms responsible for heart failure have been investigated with renewed intensity over the past several years with newer techniques of molecular genetics, genomic analysis, and cell biology. Although this article reviews some recent advances made in our understanding of molecular and cellular events in the heart leading to heart failure and explores possible new targets for therapeutics, the main point is to stress the importance of investigative interactions between organ physiologists and molecular and cellular biologists.

Age-related changes of cardiac gene expression following myocardial ischemia/reperfusion.

Young and old (4 and 25 months of age, respectively) Fisher 344/Brown Norway hybrid female rats were subjected to four 3 min episodes of ischemia separated by 5 min of reperfusion. Corresponding open-chest sham-operated groups received 32 min of no intervention. All rats were allowed to recover, and 24h later hearts were removed and frozen in liquid nitrogen.

Brief episode of ischemia activates protective genetic program in rat heart: a gene chip study.

Objective: Brief episodes of ischemia of 20 min or less have the potential to protect the heart. Such episodes are associated primarily with reversible ischemic injury yet they induce changes in gene expression. The purpose of the study was to determine whether activation of protective genes takes place within 4 h following a brief episode of ischemia that would mimic angina pectoris.

Gene expression profiling--a new approach in the study of myocardial ischemia.

Current technologies make it possible to study thousands of genes simultaneously in the same biological sample - an approach termed gene expression profiling. Several techniques, including (i) differential display, (ii) serial analysis of gene expression (SAGE), (iii) subtractive hybridization and (iv) gene microarrays (Gene Chips), have been developed. Recently, gene profiling was applied in studying the mechanisms of ischemic injury and ischemic preconditioning.